Reaction mass of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide and (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

Endpoint summary

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 - 11 November 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Limited, Bicester, Oxon, UK
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: individually housed in suspended cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 g, moistened with 0.5 ml of distilled water

Duration of treatment / exposure:

3 min (only 1st animal), 1 hour (only 1st animal) and 4 hours (all 3 animals)

Observation period:

Up to 72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: back of the animal
- Type of wrap if used: 2.5 cm x 2.5 cm cotton gauze patch and placed in position with a strip of surgical adhesive tape. To prevent the animal
interfering with the patches, the trunk of the rabbit was wrapped in an elasticated corset

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water.
- Time after start of exposure: 3 minutes, 1 hour and/or 4 hours

SCORING SYSTEM:
According to OECD guidance.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: a score of 1 at 1 hour only

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: a score of 1 at 1 hour only

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24, 48 and 72 hours

Score:

0

Irritant / corrosive response data:

Very slight erythema was noted at two treated skin sites one hour after patch removal. One treated skin site appeared normal throughout the study and the remaining two treated skin sites appeared normal at the 24-hour observation.

Other effects:

All animals showed expected gain in bodyweight during the study.

Interpretation of results:

GHS criteria not met

Conclusions:

An in vivo skin corrosion/irritation study was performed according to OECD/EC guidelines and GLP principles. As no effects were observed, it is concluded that the test substance has no corrosive or irritant effects on the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 November 2006 - 25 December 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

The pH of the test material was determined prior to commencement of the study and found to be 4.7 (10% aqueous solution). According to the Certificate of Analysis (dated 28th July 2008) the purity was re-tested (19th January 2007) and analysed to be 99.54% .

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: an accredited supplier
- Age at study initiation: twelve to twenty weeks
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: individually housed in suspended cages
- Diet: certified rabbit diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS (set conditions)
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: other (untreated) eye served as control

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 ml i.e. approximately 0.06 mg (volume measured by gently compacting the required volume into an adapted syringe)

Duration of treatment / exposure:

72 hours

Observation period (in vivo):

Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. In addition, the eyes were inspected on day 7, 14 and 21 after instillation.
Immediately after administration of the test material, an assessment of the initial pain reaction was made.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM:
Numerical evaluation according to Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.48 to 49).

TOOL USED TO ASSESS SCORE:
Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 21 days

Remarks:

At the 14-day observation, vascularisation with a localised ingrowth of vessels for approximately 3 mm around half of the cornea was noted.

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

2

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritant / corrosive response data:

Scattered or diffuse corneal opacity was noted in all treated eyes at the 24, 48 and 72-hour and 7-day observations and in one treated eye at the 14-day observation. Vascularisation, with a localised ingrowth of vessels for approximately 3 mm, around half of the cornea was noted in one treated eye at the 14-day observation. On day 21, this effect was reversed. Iridial inflammation was noted in all treated eyes one hour after treatment and at the 24-hour observation and in two treated eyes at the 48 and 72-hour observations.
Moderate conjunctival irritation was noted in all treated eyes one hour after treatment and at the 24, 48 and 72-hour observations. Minimal conjunctival irritation noted in all treated eyes at the 7-day observation and persisted in one treated eye at the 14-day observation.
Two treated eyes appeared normal at the 14-day observation and the remaining treated eye appeared normal at the 21-day observation.

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

An in vivo eye irritation study was performed according to OECD/ EC guidelines and GLP principles with 3 male rabbits. In summary, the test substance produced corneal opacity = 1 in all three animals, iritis = 1 in 2/3 animals, conjuctival redness = 2 in all three animals, which reversed in 14 days for 2 animals and in 21 days for one animal (mean of values at 24, 48 and 72 hours). Based on these results, the substance is classified Category 2 for eye irritation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available